Pharmacodynamics

Clinical Pharmacodynamics of Cannabinoids

AuthorF. Grotenhermen

AbstractOur knowledge of the pharmacodynamics of cannabinoids, that is, "the study of the biochemical and physiologic effects of drugs and their mechanisms of action" (The Merck Manual), has considerably increased within the past decade due to the detection of an endogenous cannabinoid system with specific receptors and their endogenous ligands. THC (D9-tetrahydrocannabinol), the main source of the pharmacological effects caused by the use of cannabis including the medicinal benefits of the plant, is an agonist to both the CB1 and the CB2 subtype of these receptors. Its acid metabolite THC-COOH (11-nor-9-carboxy-THC), the non-psychotropic cannabidiol (CBD), analogues of these natural compounds, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues (spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart, etc.). Additionally, there is evidence for non-receptor dependent mechanisms of cannabinoids. Five endogenous cannabinoids, anandamide, 2-arachidonylglycerol, noladine ether, virodhamine, and NADA, have been detected. There is evidence that besides the two cannabinoid receptor subtypes cloned so far, additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of endocannabinoids that include, for example, motor coordination, memory procession, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. At doses exceeding the psychotropic threshold, ingestion of exogenous CB1 receptor agonists or cannabis, respectively, usually causes an enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important potential adverse acute effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects, increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term damages on psyche and cognition, immune system, fertility and on pregnancy remain controversial. They are reported to be low in humans and do not preclude a legitimate therapeutic use of cannabis based drugs. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.